New treatment approach for influenza targets host-cell metabolism

A new study from St. Jude Children’s Research Hospital (TN, USA) has demonstrated that an investigational cancer drug may reduce the severity of influenza infection by targeting host-cell metabolism.

Flu can have serious complications in the elderly, pediatric and immunocompromized populations. This study, published recently in Cell Reports, reports a promising new approach where drugs targeting metabolism slowed viral production and increased survival in flu-infected mice.

Author Paul Thomas (St. Jude Children’s Research Hospital) commented: “Previously, little was known about how flu infection changed the metabolism of lung epithelial cells; but based on early evidence in this study we suspected metabolism was an Achilles heel of the virus. We were not disappointed.”

The team initially carried out PET scans in 20 immune-compromised pediatric cancer patients with flu or other respiratory infections, discovering that these individuals have an increased dependence on glucose and glutamine when compared with controls. The researchers further investigated this utilizing proteomic and functional analyses on primary lung cells in vitro, confirming that influenza infection alters the metabolism of human lung epithelia.

The group then screened 80 small molecule and drug candidates known to target cell metabolism, identifying BEZ235, an investigational cancer drug, which interrupted a key metabolic pathway.

Although BEZ235 did not block influenza virus from entering the host cells, the team demonstrated that BEZ235 restored PI3K and mTOR activity, which was otherwise raised during flu infection, consequently reducing viral replication. In addition, BEZ235 was demonstrated to ease respiratory symptoms and improve survival in flu-infected mouse models.

Thomas explained: “This approach works by reducing viral replication, which suggests there might be a treatment window that lasts several days in which drugs could be used to reduce the infection and risk of complications.”

The team hope that investigating the metabolic reprogramming of host cells by influenza virus may expose novel targets for treatment and also reduce the opportunities for resistance to develop. They are currently hoping to carry out additional research to determine if the approach may also be effective in targeting other respiratory viruses.

Thomas concluded: “By focusing on changing how infected cells respond to the resulting metabolic stress rather than targeting a component of the virus itself, there is less risk that the virus will become resistant to the drugs.”

Sources: Smallwood HS, Duan S, Morfouace M et al. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention. Cell Rep. doi 10.1016/j.celrep.2017.04.039 (2017) (Epub ahead of print);


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